The opium poppy, Papaver somniferum, has been used for centuries for the relief of pain and to induce sleep (Casy, A. F.; Parfitt, R. T. Opioid analgesics: chemistry and receptors; Plenum Press: New York, 1986; xv, 518). Among the most important constituents in opium are the alkaloids morphine and codeine. Many of the agonists and antagonists derived from these alkaloids are essential for the practice of modern medicine. While many potent agonists are effective analgesics, they have undesirable side effects, such as tolerance, dependence, and respiratory depression. (Stein, C.; Schafer, M.; Machelska, H. Nat. Med. 2003, 9, 1003-1008).
Endogenous opioid peptides are known and are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the processes that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, respiratory depression, learning and memory, mental illness, epileptic seizures and other neurological disorders and cardiovascular responses.
Intensive research of the last two decades has given us a better understanding of opioid receptor structure, distribution, and pharmacology (Waldhoer, M.; Bartlett, S. E.; Whistler, J. L. Annu. Rev. Biochem. 2004, 73, 953-990). Three types of opioid receptors known as mu (μ), delta, (δ), and kappa (κ) and receptor subtypes have been identified, and the mRNA encoding these receptors has been isolated. There is substantial pharmacological evidence for subtypes of each (Reisine, T. Neurotransmitter Receptors V: Opiate Receptors. Neuropharmacology 1995, 34, 463-472) It has become clear that each receptor mediates unique pharmacological responses and is differentially distributed in the central nervous system (Goldstein, A.; Naidu, A., Mol. Pharmacol. 1989, 36, 265-272; and Mansour, A.; Fox, C. A.; Akil, H.; Watson, S. J., Trends Neurosci. 1995, 18, 22-29).
The endogenous ligands for the opioid receptors are neuropeptides (Casy, A. F.; Parfitt, R. T. Opioid analgesics: chemistry and receptors; Plenum Press: New York, 1986; xv, 518). To date, three families of endogenous opioid peptides have been identified. They are classified, β-endorphins, enkephalins, and dynorphins (Gutstein, H.; Akil, H. Opioid Analgesics. Goodman & Gilman's The Pharmacological Basis of Therapeutics; 10th ed.; McGraw-Hill: New York, 2001; pp 569-619; and Eguchi, M., Med. Res. Rev. 2004, 24, 182-212). Although most of these endogenous opioids have little selectivity for opioid receptors, it is generally accepted that β-endorphins, enkephalins, and dynorphins display greater affinity for μ, δ and κ receptors respectively.
There are several structural classes of nonpeptidic opioid receptor ligands (Eguchi, M., Med. Res. Rev. 2004, 24, 182-212; Kaczor, A.; Matosiuk, D., Curr. Med. Chem. 2002, 9, 1567-1589; and Kaczor, A.; Matosiuk, D., Curr. Med. Chem., 2002, 9, 1591-1603). The oldest class of compounds are those derived from morphine (2) (FIG. 1). Examples of other structural classes include fentanyl (3), cyclazocine (4), SNC 80 (5), U50,488H (6), and 3FLB (7) (see FIG. 1). The common structural motif in all of these ligands is the presence of a basic amino group.
Salvinorin A is a unique opioid receptor ligand (1, FIG. 1). It bears little structural similarity to other structural classes of nonpeptidic opioid receptor ligands such as morphine, fentanyl, cyclazocine, SNC 80, U50,488H, and 3FLB, which all possess a basic amino group. Until recently it has been assumed that the presence of a positively charged nitrogen atom in opioid compounds represented an absolute requirement for their interaction with opioid receptors (Rees, D. C.; Hunter, J. C. Comprehensive Medicinal Chemistry; Pergammon: New York, 1990; pp 805-846). The general assumption was that this cationic amino charge on the opioid ligand would interact with the side chain carboxyl group of an aspartate residue located in TM III of the opioid receptor (Eguchi, M., Med. Res. Rev. 2004, 24, 182-212; Surratt, C.; Johnson, P.; Moriwaki, A.; Seidleck, B.; Blaschak, C. et al. J. Biol. Chem. 1994, 269, 20548-20553; and Lu, Y.; Weltrowska, G.; Lemieux, C.; Chung, N. N.; Schiller, P. W., Bioorg. Med. Chem. Lett., 2001, 11, 323-325). Given the structure and potency of salvinorin A (1), this interaction is unlikely.
Salvinorin A, originally isolated from the leaves of Salvia divinorum, was found to be very selective for κ receptors over μ and δ opioid receptors, as well as over a battery of other receptors. This was the first report of a nonnitrogenous κ opioid receptor agonist (Ortega, A.; Blount, J. F.; Manchand, P. S. Salvinorin, J. Chem. Soc. Perkin Trans. 1, 1982, 2505-2508; Valdes III, L. J.; Butler, W. M.; Hatfield, G. M.; Paul, A. G.; Koreeda, M. Divinorin A, J. Org. Chem. 1984, 49, 4716-4720; and Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C. et al., Proc. Natl. Acad. Sci. USA 2002, 99, 11934-11939).
Salvia divinorum is a plant from the Sage family that has been used in the traditional spiritual practices by the Mazatec Indians of Oaxaca, Mexico to produce “mystical” or hallucinogenic experiences (Valdes III, L. J.; Diaz, J. L.; Paul, A. G., J. Ethnopharmacol. 1983, 7, 287-312). The plant has become widely available through the internet and its recreational use by young adults and adolescents is increasing. Recipes for leaf extracts, elixirs and tincutures are easily found on the internet. Due to the recent increase in the popularity of this plant, the DEA has recently placed it on the list of drugs of concern (Center, N. D. I. Salvia divinorum. In Information Bulletin; U.S. Department of Justice: Johnstown, Pa., 2003; and Giroud, C.; Felber, F.; Augsburger, M.; Horisberger, B.; Rivier, L. et al., Forensic Sci. Int. 2000, 112, 143-150).
Currently, Salvia divinorum is unregulated in most countries and it is available throughout the world over the internet. It is listed as a controlled substance in Denmark, Australia, and Italy. At present, U.S. laws for controlled substances do not ban the use of Salvia divinorum or its active components. This has resulted in various on-line botanical companies advertising and selling Salvia divinorum as a legal alternative to other regulated plant hallucinogens.
As mentioned earlier, salvinorin A is a hallucinogen. A smoked dose of 200-500 μg produces profound hallucinations in humans (Valdes III, L. J.; Chang, H. M.; Visger, D. C.; Koreeda, M., Org. Lett. 2001, 3, 3935-3937). The potency of salvinorin A, therefore, is similar to the highly active synthetic hallucinogen LSD. However, unlike LSD and other classical hallucinogens, salvinorin A has no activity at the serotonin 5-HT2A receptor, the presumed molecular target for these compounds (Glennon, R. A.; Titeler, M.; McKenney, J. D., Life Sci. 1984, 35, 2505-2511; Titeler, M.; Lyon, R. A.; Glennon, R. A., Psychopharmacology 1988, 94, 213-216; Egan, C. T.; Herrick-Davis, K.; Miller, K.; Glennon, R. A.; Teitler, M., Psychopharmacology 1998, 136, 409-414; and Nichols, D. E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131-181).
The pharmacology of salvinorin A appears to be different than other κ agonists (Wang, Y.; Tang, K.; Inan, S.; Siebert, D. J.; Holzgrabe, U; Lee, D. Y. W.; Huang, P.; Li, J. G.; Cowan, A.; Liu-Chen, L.-Y., J. Pharmacol. Exp. Ther. 2004, 312, 220-230).
Currently, there is a need for new opioid receptor ligands that have fewer side effects than known ligands. Such ligands would be useful for the treatment of diseases and conditions associated with the activity of opioid receptors. Such ligands would also be useful as pharmacological tools for the further study of the physiological processes associated with opioid receptor structure and function.